Dense connective tissue is composed of an abundant collagen network that is maintained and repaired by fibroblasts. These fibrous tissues are commonly injured and due to poor vascularity are slow to heal, leading to over 15 million hospital visits in the U.S. each year. It's well established that dynamic mechanical stimulus will trigger fibroblasts to repair and remodel the collagen network, but the specific states of three-dimensional matrix deformation that regulate fibroblast biosynthesis have not yet been identified. One potential explanation is that fibroblast-mediated collagen remodeling is governed at the tissue-scale by distortion strain energy, which accounts for a change in matrix shape, while preserving matrix volume. To test this central hypothesis, a novel bioreactor has been developed to administer a unique combination of biaxial stresses that have previously never been applied to 3D fibroblast-seeded scaffolds. This bioreactor will be used to apply varying magnitudes of distortion energy to collagen matrices seeded with human fibroblasts for 8 days of culture. Alterations in the composition, organization, and mechanical behavior of the scaffolds will be measured. Kinematic data from the experiment will be input into a finite element model that uses matrix distortion to modulate collagen growth. Experimental and computational results will be compared for model validation. If successful, this study will provide a mechanistic basis for the repair and regeneration of dense connective tissue and will establish a new experimental and theoretical framework to study mechanosensitive cells.
The proposed project is relevant to public health because tendon and ligament tears affect over 15 million in the United States each year, and these soft connective tissues have poor healing outcomes that can lead to chronic musculoskeletal disorders. Given the impact of these injuries on workplace productivity and quality of life, there is a pressing need to help scientists and clinicians improve treatment options by identifying specific tissue deformations that stimulate the repair and regeneration of connective tissue.